CN114683658B - Surface modified scaffold and preparation method thereof - Google Patents

Abstract

The invention relates to a surface-modified stent and a preparation method thereof. The stent has a composite layer (n-layer) structure, all or not all of the n-layers are Class I electrospinning fiber membrane layers; at least one Class I electrospinning fiber membrane layer is One surface is grafted with functional substances; the preparation method is: using layer-by-layer deposition (ie, processing in n stages) to prepare a stent with a composite layer structure; after completing the i-th stage of processing to obtain an intermediate product, first process the intermediate product Carry out aminolysis-grafting modification, and then proceed to the next stage of processing, i is one, two or more positive integers in the interval [1,n]; when the product of the first stage has a hollow structure and is When the product in this stage is subjected to ammonolysis-grafting modification, its inner surface is covered with or without a water-proof conductive film. The stent of the present invention can wrap and store functional substances in specific parts as needed to extend the action time; the method of the present invention is relatively simple to operate.

Description

Surface modified scaffold and preparation method thereof

Technical field

The invention belongs to the technical field of biomedical materials and relates to a surface-modified stent and a preparation method thereof.

Background technique

The application of polymers in medicine generally requires that the processed materials have functionalized active sites. For example, blood vessels and heart valve stents require materials with anti-thrombosis, promotion of vascular cell growth, anti-inflammatory and other functions; dressings require materials prepared with Antibacterial function; the catheter material requires lubricating properties where its surface contacts the tissue, as well as anti-adhesion and other functions.

However, synthetic polymer materials such as polylactic acid (PLA), polycaprolactone (PCL), polyurethane (PU), etc. are difficult to functionalize because these synthetic polymer materials generally do not have active groups. Therefore, it is difficult to carry out functional modification directly on its surface, which also limits its application scope in medical devices.

In order to solve the above problems, the existing technology often adopts the method of coating, spraying or embedding specific drugs on the surface of medical devices made of synthetic polymer materials to give certain functions to the medical devices, or by using Medical devices made from synthetic polymer materials are surface-grafted and modified to give the medical devices certain functions.

A common problem with the coating method is that the coating is easy to fall off, which will lead to a decline in device function. The most serious problem is that if the coating fragments fall off and enter the blood circulation, they will cause adverse events such as blood clots; the spraying or embedding method There is a problem that the release rate of drugs is difficult to control. Generally, there will be a burst release in the early stage of use, and the drug release rate is slow in the middle. In the later stage, when the material degrades, a large amount of drugs will be released. These characteristics will bring many side effects and make the body function disorder. At the same time, there will also be a mismatch between the release of the drug and the demand of the tissue; relatively speaking, the surface graft modification method has unique advantages and can solve the problems of coating, spraying or embedding methods. However, surface graft modification There are still some areas for improvement in this method, mainly as follows: (1) The surface grafting modification method is only suitable for medical devices of specific shapes. The surface grafting modification method is mostly a plasma modification grafting method, which can only be used for tablets. It is difficult to graft and modify the surface of spherical and spherical medical devices, and it is difficult to graft and modify the inner surface of tubular medical devices; (2) The functional substances or groups grafted by the surface graft modification method are limited and cannot store activity. function, so the modified surface cannot function for a long time.

Therefore, it is of great significance to study a surface-modified scaffold that can solve the above problems.

Contents of the invention

The purpose of the present invention is to solve the problems existing in the prior art and provide a surface-modified stent and a preparation method thereof.

In order to achieve the above object, the scheme adopted by the present invention is as follows:

A surface-modified stent with a composite layer structure, a total of n layers of composite layers, n≥2;

The n layer is all a type I electrospinning fiber membrane layer, or a part of the n layer is a type I electrospinning fiber membrane layer, and the other part is a type II electrospinning fiber membrane layer and/or a non-porous casting layer; I The average pore size of the electrospun-like fiber membrane layer is greater than 0.5 microns, the average pore size of the type II electrospun fiber membrane layer is ≤0.5 microns, and the fiber diameter of the type II electrospinning fiber membrane layer is 100~300nm;

The material of the type I electrospun fiber membrane layer is synthetic high molecular polymer;

One surface of at least one type I electrospun fiber membrane layer is grafted with a functional substance. The functional substance is a substance that can function after the surface modified scaffold contacts tissue fluid; the type II electrospun fiber membrane layer and the non-porous No functional substances are grafted on the surface of the pouring layer.

As the preferred technical solution:

A surface modified scaffold as described above, the thickness of the type I electrospun fiber membrane layer is 50-500 microns, the thickness of the type II electrospinning fiber membrane layer is 60-120 microns, and the thickness of the non-porous casting layer It is 50 to 100 microns. It should be noted that the thickness here refers to the thickness of a single layer.

As a surface modified stent as mentioned above, the material of the type I electrospun fiber membrane layer is polylactic acid (PLA), polycaprolactone (PCL), polylactic acid caprolactone block copolymer (PLCL), polyurethane (PU) or p-dioxanone (PDO), or other aliphatic polymers, which will not be listed here; the material of the type II electrospinning fiber membrane layer is polylactic acid glycolic acid (PLGA) or Polyglycolic acid (PGA); the non-porous casting layer is made of hyaluronic acid gel or alginic acid gel.

In a surface-modified scaffold as described above, the functional substance is a substance that can release active substances after the surface-modified scaffold contacts tissue fluid, or a substance that can function in situ after the surface-modified scaffold contacts tissue fluid.

In a surface-modified scaffold as described above, the functional substance is a substance with carboxyl groups or a substance with amino groups.

A surface-modified stent as described above, the substances with carboxyl groups are SNAP (nitrosoacetyl penicillamine), heparin, heparin/X, aspirin, norfloxacin, indomethacin, naproxen, buprofen Profen, salvianolic acid, salvianoside, rebamipide or cephalosporin, among which heparin/X is heparin that binds substance X through electrostatic force; the substance with amino group is aminoglycoside drugs.

A surface-modified scaffold as described above, the substance , stellate neurokeratinocyte growth factor (AGF) or heparin-binding protein (HBP); aminoglycosides include gentamicin, tobramycin, amikacin, netilmicin, minor nomicin, isoformin, Parmicin or etilmicin.

A surface modified stent as described above, the surface modified stent is a tubular stent.

The invention also provides a method for preparing a surface-modified stent, which adopts a layer-by-layer deposition method to prepare a stent with a composite layer structure. There are n layers of composite layers, n≥2;

Layer-by-layer deposition refers to processing in n stages, and the latter stage continues processing on the product of the previous stage;

The processing at each stage is electrospinning or coating. The product of electrospinning is a type I electrospinning fiber membrane layer or a type II electrospinning fiber membrane layer. The product of the coating is a non-porous casting layer; specifically , each stage of processing is electrospinning, and the product is a Class I electrospinning fiber membrane layer; or, each stage of processing is electrospinning, and part of the product is a Class I electrospinning fiber membrane layer , the other part of the product is a type II electrospinning fiber membrane layer; or, part of the processing stage is electrospinning, and the product is a type I electrospinning fiber membrane layer, and the other part of the processing stage is coating, and the product is non-porous The pouring layer; or, part of the processing is electrospinning, and the product is a type I electrospinning fiber membrane layer, part of the processing is electrospinning, and the product is a type II electrospinning fiber membrane, and another part of the processing is electrospinning, and the product is a type II electrospinning fiber membrane. Processed into a coating, the product is a non-porous pouring layer;

After the i-th stage of processing is completed to obtain the intermediate product, the intermediate product is first subjected to aminolysis-grafting modification, and then the next stage of processing is carried out. i is one, two or more positive values in the interval [1, n]. Integer, the intermediate product is the whole composed of the products of the previous i stages; when the product of the first stage has a hollow structure and the ammonolysis-grafting modification of the first stage product is performed, the water-proof conductive film is used or not to shield Covering its inner surface, a water-proof conductive film is a film that has both water-proof and conductive properties. Its water-proof performance can ensure that the covered surface of the stent does not undergo ammonolysis-grafting modification, and its conductive properties can be used in electrospinning. Silk conducts static electricity because tin foil paper is more common, so in the present invention, it is preferred that tin foil paper is a water-proof conductive film;

The process of aminolysis-graft modification is as follows: first place the intermediate product in a diamine/alcohol solution to perform an aminolysis reaction to generate active amino groups, and then use a cross-linking agent to connect the functional substances to the active amino groups;

According to the needs of the tissue repair process, the present invention can perform grafting and functionalization of specific functional substances on specific parts of the stent. It can also graft different functional substances on different parts of the stent to exert unique functions, and then store the functional substances. The fiber membrane can be double-layered or multi-layered, and when the functional substance is a substance that can release active substances after the surface-modified scaffold contacts tissue fluid, the direction of release can be controlled as needed. In order to strictly control the direction of active substance release, An isolation layer (which can be an electrospun fiber membrane layer with very small pore size, or a non-porous casting layer, etc.) can also be added to a specific location as needed.

The structure of the surface-modified stent of the present invention is varied. Now, four structures of the surface-modified stent are exemplarily given, and their preparation methods are described in detail.

The first:

A surface-modified scaffold with a total of 2 composite layers, both of which are Class I electrospun fiber membrane layers; the inner and outer surfaces of the inner layer are grafted with functional substances, and the inner and outer surfaces of the outer layer are not grafted with functional substances. Grafting functional substances; the thickness of the outer layer is 3 to 5 times that of the inner layer, and the thickness of the inner layer is 50 to 100 microns; for materials such as vascular stents, functional substances generally work in the inner cavity of the vascular stent. If the functional substances connected to the outer wall are not blocked, the functional substances will not be able to function at the targeted position, thereby seriously affecting the function of the stent. In the stent of the present invention, both the inner and outer surfaces of the inner layer are grafted with functional substances , the functional substances grafted on the outer surface of the inner layer are tightly wrapped by the outer layer. The functional substances in this part can become a drug reservoir and extend the action time.

A method for preparing a surface-modified stent corresponding to the above-mentioned surface-modified stent, first using a cylinder (in addition to the cylinder, it can also be a cylinder-like structure or other columnar structure, the same below) as the receiving base The material is electrospun on its peripheral surface to form a layer of Class I electrospinning fiber membrane, and then the Class I electrospinning fiber membrane is removed from the cylinder and the Class I electrospinning fiber membrane is subjected to ammonolysis-grafting modification. Finally, the Type I electrospinning fiber membrane is put back on the cylinder and then electrospinning is continued on the outer surface of the Type I electrospinning fiber membrane to form another layer of Type I electrospinning fiber membrane, that is, the surface modification is obtained. Continuous spinning increases the thickness of the fiber membrane layer, and the second layer of type I electrospinning fiber membrane is several times the thickness of the first layer of type I electrospinning fiber membrane. When the functional substance is modified on the surface When the stent is able to release active substances after contacting tissue fluid, the second layer of Type I electrospun fiber membrane blocks the release of active substances to the outer wall of the tube, and it is difficult for the tissue fluid outside the tube wall to pass through the second layer of Type I electrospun fiber membrane. The silk fiber membrane reaches a thin layer site for grafting functional substances;

The process of aminolysis-graft modification is as follows: first, place the Type I electrospinning fiber membrane in a diamine/alcohol solution to perform an aminolysis reaction to generate active amino groups, and then use a cross-linking agent to connect the functional substances to the active amino groups .

As the preferred technical solution:

According to the above preparation method, the mass volume ratio of diamine to alcohol in the diamine/alcohol solution is 1 to 10g/100ml; the diamine is ethylenediamine and/or hexamethylenediamine, and the alcohol is ethanol or n-propylene. One or more of alcohol and isopropyl alcohol; the temperature of the ammonolysis reaction is 50-80°C, and the time is 1-20 minutes; after ammonolysis, the product is first rinsed with deionized water at room temperature for 3-4 hours to remove free diamine and dried under nitrogen.

According to the above preparation method, the specific process of using a cross-linking agent to connect a functional substance to an active amino group is: mixing the product of the aminolysis reaction, the functional substance and the cross-linking agent solution to perform a cross-linking reaction; The mass ratio of the cross-linking agent is 10 ^-5 ~ 10 ^-2 :1; the molar ratio of the active amino group on the ammonolysis reaction product and the amino group or carboxyl group on the functional substance is 1:1; the functional substance is carboxyl-bearing When the functional substance is a substance with an amino group, the cross-linking agent is glutaraldehyde, and the cross-linking agent is glutaraldehyde. The concentration of the agent solution is 0.5~2wt%; the temperature of the cross-linking reaction is 4°C, and the time is 0.5~1h.

Second type:

A surface-modified scaffold with a total of 2 composite layers, both of which are Class I electrospun fiber membrane layers; only the outer surface of the inner layer is grafted with functional substances, and the inner and outer surfaces of the outer layer are not grafted with functions. functional substance; the thickness of the outer layer is 0.8 to 1.5 times that of the inner layer, and the thickness of the inner layer is 200 to 300 microns; in the stent of the present invention, the thickness of the inner layer and the outer layer are close, and the functional substance is in the middle of the stent wall Therefore, the functional substance acts on the tissue at the middle position of the stent wall. When the functional substance is a substance that inhibits the excessive growth of smooth muscle cells (middle layer cells of vascular tissue), the stent of the present invention is implanted After being in vivo, it can control the proliferation rate of smooth muscle cells during the process of new blood vessel tissue formation, thereby preventing intimal hyperplasia of the vascular stent.

A method for preparing a surface-modified stent corresponding to the above-mentioned surface-modified stent. First, a cylinder is used as a receiving base material and electrospinning is performed on its peripheral surface to form a layer of Class I electrospinning fiber membrane. The peripheral surface of the cylinder Completely wrap the water-isolating conductive film, and then remove the type I electrospun fiber membrane from the cylinder together with the water-isolating conductive film, and then perform ammonolysis-grafting modification of the type I electrospinning fiber membrane (during this process The water-proof conductive film is close to the inner surface of the Class I electrospun fiber membrane, which avoids ammonolysis-grafting modification of the inner surface). Finally, the Class I electrospun fiber membrane is re-sheathed together with the water-blocking conductive film. After the cylinder is attached, electrospinning is continued on the outer surface of the Class I electrospinning fiber membrane to form another layer of Class I electrospinning fiber membrane, thereby obtaining a surface modified scaffold;

The process of aminolysis-graft modification is as follows: first, place the Type I electrospinning fiber membrane in a diamine/alcohol solution to perform an aminolysis reaction to generate active amino groups, and then use a cross-linking agent to connect the functional substances to the active amino groups .

As the preferred technical solution:

According to the above preparation method, the mass volume ratio of diamine to alcohol in the diamine/alcohol solution is 1 to 10g/100ml; the diamine is ethylenediamine and/or hexamethylenediamine, and the alcohol is ethanol or n-propylene. One or more of alcohol and isopropyl alcohol; the temperature of the ammonolysis reaction is 50-80°C, and the time is 1-20 minutes; after ammonolysis, the product is first rinsed with deionized water at room temperature for 3-4 hours to remove free diamine and dried under nitrogen.

According to the above preparation method, the specific process of using a cross-linking agent to connect a functional substance to an active amino group is: mixing the product of the aminolysis reaction, the functional substance and the cross-linking agent solution to perform a cross-linking reaction; The mass ratio of the cross-linking agent is 10 ^-5 ~ 10 ^-2 :1; the molar ratio of the active amino group on the ammonolysis reaction product and the amino group or carboxyl group on the functional substance is 1:1; the functional substance is carboxyl-bearing When the functional substance is a substance with an amino group, the cross-linking agent is glutaraldehyde, and the cross-linking agent is glutaraldehyde. The concentration of the agent solution is 0.5~2wt%; the temperature of the cross-linking reaction is 4°C, and the time is 0.5~1h.

The third type:

A surface-modified scaffold with a total of 2 composite layers, both of which are Class I electrospun fiber membrane layers; only the outer surface of the inner layer is grafted with functional substances, and the outer layer is only grafted with functional substances on the outer surface; The thickness of the outer layer is 20-60 microns, and the thickness of the inner layer is 300-500 microns; in the stent of the present invention, part of the functional substances is located outside the stent wall, and the other part of the functional substances is stored in the middle of the stent wall In this way, when the functional substance is a substance that can release active substances after the surface-modified stent contacts tissue fluid, the functional substance can more easily release active substances to the outside of the stent to play a role, such as connecting The specific functional substances of the branches can release active substances that inhibit the invasion of a large number of fibroblasts and avoid fibrosis of the scaffold and tissue.

A method for preparing a surface-modified stent corresponding to the above-mentioned surface-modified stent. First, a cylinder is used as a receiving base material and electrospinning is performed on its peripheral surface to form a first layer of Class I electrospinning fiber membrane. Completely wrap the water-isolating conductive film on the surface, and then remove the first layer of Class I electrospun fiber membrane from the cylinder together with the water-isolating conductive film, and then conduct ammonolysis-grafting of the first layer of Class I electrospinning fiber membrane. Modification (during this process, the water-proof conductive film is close to the inner surface of the Class I electrospinning fiber membrane, avoiding ammonolysis-grafting modification of the inner surface), and then the Class I electrostatic fiber membrane is added together with the water-blocking conductive film. After the spinning fiber membrane is put on the cylinder again, electrospinning is continued on the outer surface of the first layer of Class I electrospinning fiber membrane without removing the water-proof conductive membrane to form a second layer of Class I electrospinning fiber. The membrane obtains an intermediate product containing a water-isolating conductive membrane, and finally the intermediate product containing a water-isolating conductive membrane is subjected to ammonolysis-grafting modification (during this process, the water-isolating conductive membrane adheres closely to the inner surface of the Class I electrospinning fiber membrane , avoiding the ammonolysis-grafting modification of its inner surface) and then removing the water-proof conductive film to obtain a surface-modified stent;

The process of ammonolysis-graft modification is as follows: first, place the first layer of Class I electrospinning fiber membrane or the intermediate product containing a water-barrier conductive membrane in a diamine/alcohol solution to perform an ammonolysis reaction to generate active amino groups, and then Use cross-linking agents to connect functional substances with active amino groups.

As the preferred technical solution:

According to the above preparation method, the mass volume ratio of diamine to alcohol in the diamine/alcohol solution is 1 to 10g/100ml; the diamine is ethylenediamine and/or hexamethylenediamine, and the alcohol is ethanol or n-propylene. One or more of alcohol and isopropyl alcohol; the temperature of the ammonolysis reaction is 50-80°C, and the time is 1-20 minutes; after ammonolysis, the product is first rinsed with deionized water at room temperature for 3-4 hours to remove free diamine and dried under nitrogen.

According to the above preparation method, the specific process of using a cross-linking agent to connect a functional substance to an active amino group is: mixing the product of the aminolysis reaction, the functional substance and the cross-linking agent solution to perform a cross-linking reaction; The mass ratio of the cross-linking agent is 10 ^-5 ~ 10 ^-2 :1; the molar ratio of the active amino group on the ammonolysis reaction product and the amino group or carboxyl group on the functional substance is 1:1; the functional substance is carboxyl-bearing When the functional substance is a substance with an amino group, the cross-linking agent is glutaraldehyde, and the cross-linking agent is glutaraldehyde. The concentration of the agent solution is 0.5~2wt%; the temperature of the cross-linking reaction is 4°C, and the time is 0.5~1h.

The fourth type;

A surface-modified scaffold with a total of three composite layers. The inner and outer layers are both Class I electrospun fiber membrane layers, and the middle layer is a Class II electrospun fiber membrane layer or a non-porous casting layer; the inner layer Both the inner and outer surfaces are grafted with functional substances, and the inner and outer surfaces of the outer layer are not grafted with functional substances; the thickness of the outer layer is 100 to 300 microns, the thickness of the middle layer is 50 to 120 microns, and the thickness of the inner layer is The thickness is 100 to 300 microns; in the stent of the present invention, part of the functional substances are located inside the stent wall, and the other part of the functional substances are stored in the middle of the stent wall as a drug reservoir, and the middle layer is an isolation layer. The inner and outer layers are separated so that the stored functional substances can continue to perform their functions later.

A method for preparing a surface-modified stent corresponding to the above-mentioned surface-modified stent. First, a cylinder is used as a receiving base material and electrospinning is performed on its peripheral surface to form a layer of Class I electrospinning fiber membrane. After removing the Type I electrospinning fiber membrane, perform ammonolysis-grafting modification on the Type I electrospinning fiber membrane, then put the Type I electrospinning fiber membrane back on the cylinder and then add the Type I electrospinning fiber The outer surface of the membrane is electrospun to form a type II electrospun fiber membrane, or a non-porous casting layer is formed through coating, and finally electrospinning is performed on the outer surface of the type II electrospinning fiber membrane or non-porous casting layer Form another layer of Class I electrospinning fiber membrane to obtain a surface-modified scaffold;

The process of aminolysis-graft modification is as follows: first, place the Type I electrospinning fiber membrane in a diamine/alcohol solution to perform an aminolysis reaction to generate active amino groups, and then use a cross-linking agent to connect the functional substances to the active amino groups .

As the preferred technical solution:

According to the above preparation method, the electrospinning process parameters corresponding to the Class I electrospinning fiber membrane are: the concentration of the spinning liquid is 8-25wt%, the spinning voltage is 10-30kV, and the spinning advancement speed is 1.0-2.5mL/ h, the diameter of the cylinder receiving base material is ≥1mm, the receiving distance is 8~25cm, and the rotation speed is 50~500rpm;

The electrospinning process parameters corresponding to the Type II electrospinning fiber membrane are: the concentration of the spinning solution is 3 to 8 wt%, the spinning voltage is 8 to 20 kV, the spinning advancement speed is 0.5 to 1.0 mL/h, and the cylinder receives the substrate The diameter is ≥1mm, the receiving distance is 8~25cm, and the rotation speed is 50~500rpm;

The specific process of coating to form a non-porous casting layer is as follows: disconnect the high-voltage power supply of the electrospinning equipment while keeping the receiving substrate continuing to rotate, and add a hyaluronic acid or alginic acid polysaccharide solution with a concentration of 1 to 5 wt%. Put it into a syringe, extrude it through a push pump, and deposit it on the outer surface of the type I electrospun fiber membrane; the number average molecular weight of hyaluronic acid or alginic acid polysaccharide is 200,000 to 1 million, and the extrusion speed is 3 to 5 mL. /h.

According to the above preparation method, the mass volume ratio of diamine to alcohol in the diamine/alcohol solution is 1 to 10g/100ml; the diamine is ethylenediamine and/or hexamethylenediamine, and the alcohol is ethanol or n-propylene. One or more of alcohol and isopropyl alcohol; the temperature of the ammonolysis reaction is 50-80°C, and the time is 1-20 minutes; after ammonolysis, the product is first rinsed with deionized water at room temperature for 3-4 hours to remove free diamine and dried under nitrogen.

According to the above preparation method, the specific process of using a cross-linking agent to connect a functional substance to an active amino group is: mixing the product of the aminolysis reaction, the functional substance and the cross-linking agent solution to perform a cross-linking reaction; The mass ratio of the cross-linking agent is 10 ^-5 ~ 10 ^-2 :1; the molar ratio of the active amino group on the ammonolysis reaction product and the amino group or carboxyl group on the functional substance is 1:1; the functional substance is carboxyl-bearing When the functional substance is a substance with an amino group, the cross-linking agent is glutaraldehyde, and the cross-linking agent is glutaraldehyde. The concentration of the agent solution is 0.5~2wt%; the temperature of the cross-linking reaction is 4℃, and the time is 0.5~1h.

The principle of the present invention is:

The characteristic of surface grafting modification is that the functional substances grafted on the surface of the material are relatively stable (involving the formation of covalent chemical bonds) and can function under appropriate conditions.

In general, surface grafting is more difficult to modify specific parts of the tubular stent, especially grafting on special parts such as the inner wall and middle part of the tubular stent. For example, in the existing plasma modification grafting method, the plasma will It is difficult to create some active groups on the surface of the stent, but for the inner wall of the tubular stent, the instrument is difficult to achieve, and it is even more impossible to operate the middle position of the tube wall. The present invention adopts the ammonolysis-grafting modification method to solve the problems existing in the prior art. Since the entire stent is immersed in the reaction liquid during the ammonolysis-grafting modification process, both the inner and outer surfaces of the stent can come into contact with the reaction liquid, resulting in The active group then undergoes subsequent functional substance connection.

In addition, there is a problem with surface grafting, that is, the amount of surface grafting is quite limited, so the functionalized surface has a limited time to function when in contact with tissue. In surface graft modification, the amount of grafting mainly depends on two factors. The first is the surface area that participates in the modification, and the second is the length of the reaction time during modification; for scaffolds, the surface area that can participate in the modification is limited. The reaction time during modification is within a certain range. As the reaction time increases during modification, the amount of active groups produced also increases, which means that the amount of functional substances grafted also increases, but the reaction There will always be a limit, and increasing the reaction time after that will not increase the amount. In the preparation process of the stent, the present invention adopts electrospinning technology combined with ammonolysis technology. It does not carry out ammonolysis modification grafting on a certain surface of the stent after the preparation is complete, but in the process of preparing the stent, Aminolysis grafting can be carried out at designated parts, and the reaction can be carried out in stages or multiple times as needed. In this way, the total amount of active amino groups produced will increase, and theoretically the amount of functional substances to be grafted will also increase. In the design of the present invention, the inner wall, middle or outer wall of the stent tube wall can be modified, and the site where the functional substance acts can be controlled, allowing the functional substance to be stored in different locations. When the functional substance is on the surface When the modified scaffold is able to release active substances after contacting tissue fluid, it can achieve a slow release effect and can control the release of functional substances in a specific direction. Functional substances will cause their release in the body environment, especially when they come into contact with tissue fluid. To exert its function, the part that is not in direct contact with tissue fluid will subsequently slowly release active substances into the lumen of the tubular stent through the thin fiber pores and continue to perform its function.

Although within a certain range, the longer the amino group is, the more active amino groups will be produced, but the solution will also destroy part of the structure of the scaffold and affect the mechanics and other properties of the scaffold to a certain extent. In the present invention, electrospinning is performed after ammonia decomposition The wire can further strengthen the overall mechanical properties of the stent and compensate for the adverse effects caused by ammonolysis.

beneficial effects

(1) The stent of the present invention can be grafted with one or more functional substances at multiple locations as needed, and the number of grafts is greatly increased. Wrapping and storing functional substances in specific locations in the fiber can extend the action time and also Can function in one direction;

(2) The method of the present invention is relatively simple to operate, and the modification method can control the grafting amount of functional substances. This method is not only suitable for various types of tubular stents, but can also be used for non-tubular stents.

Description of drawings

Figure 1 is a schematic diagram of the preparation of the surface-modified stent of Example 1;

Figure 2 is a schematic diagram of the preparation of the surface-modified stent of Example 3;

Figure 3 is a schematic diagram of the preparation of the surface-modified stent of Example 5;

Figure 4 is a schematic diagram of the preparation of the surface-modified stent of Example 7;

Figure 5 is a schematic diagram of the preparation of the surface-modified stent in Example 9.

Detailed ways

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the invention and are not intended to limit the scope of the invention. In addition, it should be understood that after reading the teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

The "molar amount of active amino groups on the product of the ammonolysis reaction" in the following examples is measured by the ninhydrin assay. The specific process is: put the product of the ammonolysis reaction into a 2 mL container with a concentration of 0.1 mol/L ninhydrin/ethanol solution in a glass tube, and reacted at 80°C for 15 minutes to generate purple crystals, and then add 8 mL of 1,4-dioxane to the tube to dissolve the product of the ammonolysis reaction to form Purple crystal, and then use UV spectrophotometry to measure the absorbance value of the solution. By comparing it with the absorbance value of the standard solution, the molar amount of active amino groups on the product of the ammonolysis reaction can be obtained.

Example 1

A method for preparing a surface-modified stent, as shown in Figure 1. The specific steps are as follows:

(1) Use a cylinder as the receiving base material and perform electrospinning on its peripheral surface to form a layer of Class I electrospinning fiber membrane with a thickness of 50 microns and an average pore diameter of 6.3 microns;

The process parameters of electrospinning are: the concentration of the spinning solution is 25wt%, the spinning voltage is 30kV, the spinning advancement speed is 2.5mL/h, the diameter of the cylinder receiving the substrate is 1mm, the receiving distance is 25cm, and the rotation speed is 500rpm;

The polymer in the spinning solution is polylactic acid with a number average molecular weight of 100,000;

(2) Remove the Type I electrospun fiber membrane from the cylinder and perform ammonolysis-grafting modification of the Type I electrospun fiber membrane;

The process of aminolysis-graft modification is as follows: first, place the type I electrospun fiber membrane in a n-propanol solution of hexamethylenediamine with a mass-to-volume ratio of 10g/100mL, conduct an aminolysis reaction at 80°C for 1 minute, and then The product of the ammonolysis reaction, heparin and the cross-linking agent aqueous solution are mixed and the cross-linking reaction is carried out. Finally, an aqueous solution of the growth factor AGF with a concentration of 100ng/mL is used to infiltrate the surface of the cross-linking reaction product for 30 minutes to allow heparin to bind to the growth factor AGF. (The product is recorded as heparin/AGF);

Among them, the mass ratio of heparin to the cross-linking agent is 10 ^-5 :1; the molar ratio of the active amino group on the aminolysis reaction product to the carboxyl group on the heparin is 1:1; the cross-linking agent is a mass ratio of 3:2 For EDC and NHS, the concentration of the cross-linking agent aqueous solution is 5wt%; the cross-linking reaction temperature is 4°C and the time is 1 hour;

(3) Place the Type I electrospun fiber membrane on the cylinder again and continue electrospinning on the outer surface of the Type I electrospun fiber membrane to form another layer of I with a thickness of 250 microns and an average pore size of 3.7 microns. Similar to electrospun fiber membrane, the surface modified scaffold is obtained;

The process parameters of electrospinning are: the concentration of the spinning solution is 25wt%, the spinning voltage is 30kV, the spinning advancement speed is 2.5mL/h, the diameter of the cylinder receiving the substrate is 1mm, the receiving distance is 25cm, and the rotation speed is 500rpm;

The polymer in the spinning solution is polylactic acid with a number average molecular weight of 100,000.

The final surface-modified stent is a tubular stent with a composite layer structure. There are 2 composite layers in total, and both layers are Type I electrospun fiber membrane layers; both the inner and outer surfaces of the inner layer are grafted. There is heparin/AGF, but neither the inner nor outer surface of the outer layer is grafted with heparin/AGF.

The final surface-modified scaffold can be used as a peripheral nerve conduit. The release of AGF into the lumen directly or through a large-pore film will induce the nerve axons to extend into the lumen and accelerate the repair of nerve tissue. Since both the inner and outer surfaces of the inner layer are grafted with heparin/AGF, part of the AGF can be stored first and then continue to be released through the large pores of the thin layer. The action time can reach 3 to 4 weeks; in comparison, if Only the inner surface of the inner layer is grafted with heparin/AGF, and AGF is basically consumed within 1 week. Therefore, this kind of scaffold can extend the action time of the drug and better match the nerve tissue repair process.

Example 2

A method for preparing a surface-modified stent. The specific steps are as follows:

(1) Using a cylinder as the receiving substrate, perform electrospinning on its peripheral surface to form a layer of Class I electrospun fiber membrane with a thickness of 100 microns and an average pore diameter of 5.4 microns;

The process parameters of electrospinning are: the concentration of spinning liquid is 8wt%, the spinning voltage is 10kV, the spinning advancement speed is 1mL/h, the diameter of the cylinder receiving the substrate is 2.5mm, the receiving distance is 8cm, and the rotation speed is 50rpm;

The polymer in the spinning solution is polycaprolactone with a number average molecular weight of 500,000;

(2) Remove the Type I electrospun fiber membrane from the cylinder and perform ammonolysis-grafting modification of the Type I electrospun fiber membrane;

The process of aminolysis-grafting modification is as follows: first, place the type I electrospun fiber membrane in an ethanol solution of diethylenediamine with a mass-to-volume ratio of 1g/100mL, then perform an aminolysis reaction at 50°C for 20 minutes, and finally Mix the product of the aminolysis reaction, SNAP and the cross-linking agent aqueous solution to perform a cross-linking reaction;

The mass ratio of SNAP to the crosslinking agent is 10 ^-2 :1; the molar ratio of the active amino group on the product of the aminolysis reaction to the carboxyl group on the SNAP is 1:1; the crosslinking agent is EDC and NHS in a mass ratio of 3:2, and the concentration of the crosslinking agent aqueous solution is 20wt%; the temperature of the crosslinking reaction is 4°C, and the time is 0.5h;

(3) Place the Type I electrospun fiber membrane on the cylinder again and continue electrospinning on the outer surface of the Type I electrospun fiber membrane to form another layer of I with a thickness of 300 microns and an average pore size of 3.3 microns. Similar to electrospun fiber membrane, the surface modified scaffold is obtained;

The process parameters of electrospinning are: the concentration of spinning liquid is 8wt%, the spinning voltage is 10kV, the spinning advancement speed is 1mL/h, the diameter of the cylinder receiving the substrate is 2.5mm, the receiving distance is 8cm, and the rotation speed is 50rpm;

The polymer in the spinning solution is polycaprolactone with a number average molecular weight of 500,000.

The final surface-modified stent is a tubular stent with a composite layer structure. There are 2 composite layers in total, and both layers are Type I electrospun fiber membrane layers; both the inner and outer surfaces of the inner layer are grafted. With SNAP, the inner and outer surfaces of the outer layer are not grafted with SNAP.

The finally prepared surface-modified stent can be used as a cardiovascular stent. SNAP releases NO under physiological conditions and releases it into the lumen through the macroporous film, which can prevent platelet adhesion and promote endothelialization, thereby accelerating cardiac arrest. Repair of vascular tissue. The grafted SNAP on the inner surface of the inner layer of the stent is in direct contact with the blood and will basically lose its efficacy after one week. The stent is grafted with SNAP on both the inner and outer surfaces of the inner layer of the stent, so the SNAP on the outer surface will be stored. Since there is no direct contact with the blood, NO will be released relatively slowly and penetrate through the gaps in the thin layer. comes out, ultimately extending the duration of action up to 3 weeks.

Example 3

A method for preparing a surface-modified stent, as shown in Figure 2. The specific steps are as follows:

(1) Use a cylinder with the circumference completely wrapped in tin foil as the receiving base material and perform electrospinning on its circumference to form a layer of Class I electrospun fiber membrane with a thickness of 200 microns and an average pore size of 3.8 microns;

The process parameters of electrospinning are: the concentration of the spinning solution is 10wt%, the spinning voltage is 20kV, the spinning advancement speed is 2mL/h, the diameter of the cylinder receiving the substrate is 4mm, the receiving distance is 20cm, and the rotation speed is 400rpm;

The polymer in the spinning solution is a polylactate caprolactone block copolymer with a number average molecular weight of 400,000 and a segment molar ratio of 1:1;

(2) After removing the Type I electrospun fiber membrane from the cylinder together with the tin foil paper, perform ammonolysis-grafting modification of the Type I electrospun fiber membrane;

The process of aminolysis-graft modification is as follows: first, place the type I electrospinning fiber membrane in a n-propanol solution of hexamethylenediamine with a mass-to-volume ratio of 10g/100mL, and then perform an aminolysis reaction at 80°C for 1 minute. Finally, the product of the aminolysis reaction, heparin and the cross-linking agent aqueous solution are mixed and the cross-linking reaction is performed;

The mass ratio of heparin to cross-linking agent is 10 ^-5 :1; the molar ratio of the active amino group on the aminolysis reaction product to the carboxyl group on heparin is 1:1; the cross-linking agent is EDC and EDC with a mass ratio of 3:2. NHS, the concentration of the cross-linking agent aqueous solution is 5wt%; the cross-linking reaction temperature is 4°C and the time is 0.6h;

(3) Place the Type I electrospun fiber membrane on the cylinder again and continue electrospinning on the outer surface of the Type I electrospun fiber membrane to form another layer of I with a thickness of 300 microns and an average pore size of 3.2 microns. Similar to electrospun fiber membrane, the surface modified scaffold is obtained;

The process parameters of electrospinning are: the concentration of the spinning solution is 10wt%, the spinning voltage is 20kV, the spinning advancement speed is 2mL/h, the diameter of the cylinder receiving the substrate is 4mm, the receiving distance is 20cm, and the rotation speed is 400rpm;

The polymer in the spinning solution is a polylactate caprolactone block copolymer with a number average molecular weight of 400,000 and a molar ratio of 1:1.

The prepared surface-modified stent is a tubular stent with a composite layer structure. The composite layer has a total of 2 layers, both of which are Class I electrospun fiber membrane layers; only the outer surface of the inner layer is grafted with Heparin, neither the inner nor outer surface of the outer layer is grafted with heparin.

The finally prepared surface-modified stent can be used as a cardiovascular stent. Heparin is located in the middle of the wall of the vascular stent, which can inhibit the excessive proliferation of smooth muscle cells during the formation of new blood vessels, thereby reducing the internal stress that occurs in the formation of new blood vessels. The problem of membrane proliferation ensures the normal functionalization of neovascular tissue.

Example 4

A method for preparing a surface-modified stent. The specific steps are as follows:

(1) Use a cylinder with the circumference completely wrapped in tin foil as the receiving base material, and perform electrospinning on its circumference to form a layer of Class I electrospun fiber membrane with a thickness of 200 microns and an average pore size of 4.3 microns;

The process parameters of electrospinning are: the concentration of spinning liquid is 20wt%, the spinning voltage is 15kV, the spinning advancement speed is 1.5mL/h, the diameter of the cylinder receiving the substrate is 6mm, the receiving distance is 12cm, and the rotation speed is 100rpm;

The polymer in the spinning solution is polyurethane with a number average molecular weight of 200,000;

(2) After removing the Type I electrospun fiber membrane from the cylinder together with the tin foil paper, perform ammonolysis-grafting modification of the Type I electrospun fiber membrane;

The process of aminolysis-grafting modification is as follows: first, place the type I electrospinning fiber membrane in an isopropyl alcohol solution of hexamethylenediamine with a mass-to-volume ratio of 3g/100mL, and then perform an aminolysis reaction at 60°C for 7 minutes. Finally, the product of the ammonolysis reaction, gentamicin and the aqueous solution of the cross-linking agent are mixed to perform a cross-linking reaction;

The mass ratio of gentamicin to cross-linking agent is 10 ^-4 :1; the molar ratio of the active amino group on the product of the aminolysis reaction to the amino group on gentamicin is 1:1; the cross-linking agent is glutaraldehyde , the concentration of the cross-linking agent aqueous solution is 0.5wt%; the cross-linking reaction temperature is 4°C and the time is 0.5h;

(3) Place the Type I electrospun fiber membrane on the cylinder again and continue electrospinning on the outer surface of the Type I electrospun fiber membrane to form another layer of I with a thickness of 240 microns and an average pore size of 4 microns. Similar to electrospun fiber membrane, the surface modified scaffold is obtained;

The process parameters of electrospinning are: the concentration of spinning liquid is 20wt%, the spinning voltage is 15kV, the spinning advancement speed is 1.5mL/h, the diameter of the cylinder receiving the substrate is 6mm, the receiving distance is 12cm, and the rotation speed is 100rpm;

The polymer in the spinning solution is polyurethane with a number average molecular weight of 200,000.

The prepared surface-modified stent is a tubular stent with a composite layer structure. The composite layer has a total of 2 layers, both of which are Class I electrospun fiber membrane layers; only the outer surface of the inner layer is grafted with Gentamicin, neither the inner nor outer surface of the outer layer is grafted with gentamicin.

The final surface-modified stent can be used as a urethra or ureteral stent. Gentamicin is located in the middle of the wall of the vascular stent, which can inhibit urethral infection and accelerate tissue reconstruction during the formation of new urethral tissue. Antibiotics are generally injected within a period of time after surgery, so the presence of antibiotics in the middle of the stent wall plays an anti-infective role during the tissue reconstruction process (mid-late period).

Example 5

A method for preparing a surface-modified stent, as shown in Figure 3. The specific steps are as follows:

(1) Use a cylinder with the circumference completely wrapped in tin foil as the receiving base material, and perform electrospinning on its circumference to form the first layer of Class I electrospun fiber membrane with a thickness of 300 microns and an average pore diameter of 3.3 microns;

The process parameters of electrospinning are: the concentration of the spinning solution is 13wt%, the spinning voltage is 18kV, the spinning advancement speed is 1.8mL/h, the diameter of the cylinder receiving the substrate is 5mm, the receiving distance is 19cm, and the rotation speed is 380rpm;

The polymer in the spinning solution is polyurethane with a number average molecular weight of 250,000;

(2) Then remove the first layer of Class I electrospun fiber membrane from the cylinder together with the tin foil paper, and then perform ammonolysis-grafting modification on the first layer of Class I electrospun fiber membrane;

The process of ammonolysis-grafting modification of the first layer of Class I electrospun fiber membrane is as follows: first, place the Class I electrospun fiber membrane in an ethanol solution of ethylenediamine with a mass to volume ratio of 8g/100mL. Then perform an aminolysis reaction at 65°C for 16 minutes, and finally mix the product of the aminolysis reaction, aspirin and the aqueous solution of the cross-linking agent to perform the cross-linking reaction;

The mass ratio of aspirin to cross-linking agent is 10 ^-3 :1; the molar ratio of the active amino group on the aminolysis reaction product to the carboxyl group on aspirin is 1:1; the cross-linking agent is EDC and EDC with a mass ratio of 3:2. NHS, the concentration of the cross-linking agent aqueous solution is 18wt%; the cross-linking reaction temperature is 4°C and the time is 0.8h;

(3) Then, without removing the tin foil, continue electrospinning on the outer surface of the first layer of Class I electrospinning fiber membrane to form a second layer of Class I electrospun fiber membrane with a thickness of 60 microns and an average pore size of 5.7 microns. The silk fiber membrane is used to obtain an intermediate product containing tin foil;

The process parameters of electrospinning are: the concentration of the spinning solution is 13wt%, the spinning voltage is 18kV, the spinning advancement speed is 1.8mL/h, the diameter of the cylinder receiving the substrate is 5mm, the receiving distance is 19cm, and the rotation speed is 380rpm;

The polymer in the spinning solution is polyurethane with a number average molecular weight of 250,000;

(4) Perform aminolysis-graft modification on the intermediate product containing tin foil paper and then remove the tin foil paper to obtain a surface-modified scaffold;

The process of ammonolysis-graft modification of the intermediate product containing tin foil paper is as follows: first, place the intermediate product containing tin foil paper in an ethanol solution of ethylenediamine with a mass to volume ratio of 8g/100mL, and then place it at 65°C The ammonolysis reaction is carried out for 16 minutes, and finally the product of the ammonolysis reaction, tobramycin and the aqueous solution of the cross-linking agent are mixed and the cross-linking reaction is carried out;

The mass ratio of tobramycin to cross-linking agent is 10 ^-4 :1; the molar ratio of the active amino group on the aminolysis reaction product to the amino group on tobramycin is 1:1; the cross-linking agent is glutaraldehyde , the concentration of the cross-linking agent aqueous solution is 0.5wt%; the cross-linking reaction temperature is 4°C and the time is 0.5h.

The prepared surface-modified stent is a tubular stent with a composite layer structure. The composite layer has a total of 2 layers, both of which are Class I electrospun fiber membrane layers; only the outer surface of the inner layer is grafted with Aspirin, only the outer surface of the outer layer is grafted with tobramycin.

The final surface-modified stent can be used as a bile duct stent. Aspirin has an anti-inflammatory effect, while tobramycin is an antibacterial agent. The combination of the two drugs can prevent infection during the biliary repair process.

Example 6

A method for preparing a surface-modified stent. The specific steps are as follows:

(1) Use a cylinder with the circumferential surface completely wrapped in tin foil as the receiving base material and perform electrospinning on its circumferential surface to form the first layer of Class I electrospun fiber membrane with a thickness of 500 microns and an average pore diameter of 1.9 microns;

The process parameters of electrospinning are: the concentration of the spinning solution is 18wt%, the spinning voltage is 17kV, the spinning advancement speed is 1.6mL/h, the diameter of the cylinder receiving the substrate is 16mm, the receiving distance is 13cm, and the rotation speed is 110rpm;

The polymer in the spinning solution is dioxanone with a number average molecular weight of 350,000;

(2) Then remove the first layer of Class I electrospun fiber membrane from the cylinder together with the tin foil paper, and then perform ammonolysis-grafting modification on the first layer of Class I electrospun fiber membrane;

The process of ammonolysis-grafting modification of the first layer of Class I electrospun fiber membrane is as follows: first, place the Class I electrospun fiber membrane in an isopropyl alcohol solution of hexamethylenediamine with a mass to volume ratio of 5g/100mL. in, then conduct an aminolysis reaction at 55°C for 15 minutes, and finally mix the product of the aminolysis reaction, norfloxacin and the aqueous solution of the cross-linking agent to perform the cross-linking reaction;

The mass ratio of norfloxacin and cross-linking agent is 10 ^-4 :1; the molar ratio of the active amino group on the ammonolysis reaction product and the carboxyl group on norfloxacin is 1:1; the mass ratio of the cross-linking agent is 3:2 EDC and NHS, the concentration of the cross-linking agent aqueous solution is 9wt%; the cross-linking reaction temperature is 4°C and the time is 0.9h;

(3) Then, without removing the tin foil, continue electrospinning on the outer surface of the first layer of Class I electrospinning fiber membrane to form a second layer of Class I electrospun fiber membrane with a thickness of 30 microns and an average pore size of 7.2 microns. The silk fiber membrane is used to obtain an intermediate product containing tin foil;

The process parameters of electrospinning are: the concentration of the spinning solution is 18wt%, the spinning voltage is 17kV, the spinning advancement speed is 1.6mL/h, the diameter of the cylinder receiving the substrate is 16mm, the receiving distance is 13cm, and the rotation speed is 110rpm;

The polymer in the spinning solution is dioxanone with a number average molecular weight of 350,000;

(4) Perform aminolysis-graft modification on the intermediate product containing tin foil paper and then remove the tin foil paper to obtain a surface-modified scaffold;

The process of aminolysis-graft modification of the intermediate product containing tin foil paper is basically the same as the process of aminolysis-graft modification of the first layer of type I electrospun fiber membrane, the only difference is that salvianolic acid is used Alternative to norfloxacin.

The prepared surface-modified stent is a tubular stent with a composite layer structure. The composite layer has a total of 2 layers, both of which are Class I electrospun fiber membrane layers; only the outer surface of the inner layer is grafted with For norfloxacin, only the outer surface of the outer layer is grafted with salvianolic acid.

The final surface-modified stent can be used as a tracheal stent in the respiratory system. The outer layer is grafted with the salvia miltiorrhiza drug salvianolic acid, which can inhibit tissue fibrosis. The outer surface of the inner layer is grafted with the antibiotic norfloxacin. Since the outer layer of the stent is only 30 microns thick, the norfloxacin on the outer surface of the inner layer can play an antibacterial effect on the outer wall of the stent.

Example 7

A method for preparing a surface-modified stent, as shown in Figure 4. The specific steps are as follows:

(1) Using a cylinder as the receiving base material, perform electrospinning on its peripheral surface to form a layer of Class I electrospun fiber membrane with a thickness of 100 microns and an average pore diameter of 5.4 microns;

The process parameters of electrospinning are: the concentration of the spinning solution is 15wt%, the spinning voltage is 20kV, the spinning advancement speed is 1.5mL/h, the diameter of the cylinder receiving the substrate is 7mm, the receiving distance is 15cm, and the rotation speed is 200rpm;

The polymer in the spinning solution is polylactic acid with a number average molecular weight of 300,000;

(2) Aminolysis-grafting modification of type I electrospun fiber membrane;

The process of aminolysis-graft modification is as follows: first, place the type I electrospinning fiber membrane in an ethanol solution of ethylenediamine with a mass-to-volume ratio of 5g/100mL, then perform an aminolysis reaction at 80°C for 1 minute, and then The product of the ammonolysis reaction, heparin and the aqueous solution of the cross-linking agent are mixed and then cross-linked. Finally, a growth factor bFGF solution with a concentration of 200ng/mL will be used to infiltrate the surface of the cross-linked reaction product for 30 minutes to allow heparin to combine with the growth factor bFGF ( The product is recorded as heparin/bFGF);

Among them, the mass ratio of heparin to the cross-linking agent is 10 ^-5 :1; the molar ratio of the active amino group on the aminolysis reaction product to the carboxyl group on the heparin is 1:1; the cross-linking agent is a mass ratio of 3:2 For EDC and NHS, the concentration of the cross-linking agent aqueous solution is 5wt%; the cross-linking reaction temperature is 4°C and the time is 1 hour;

(3) Form a Type II electrospun fiber membrane with a thickness of 120 microns and an average pore size of 0.3 microns on the outer surface of the Type I electrospun fiber membrane through electrospinning;

The process parameters of electrospinning are: the concentration of spinning liquid is 3wt%, the spinning voltage is 20kV, the spinning advancement speed is 1mL/h, the diameter of the cylinder receiving the substrate is 7mm, the receiving distance is 25cm, and the rotation speed is 500rpm;

The polymer in the spinning solution is polylactic acid glycolic acid with a number average molecular weight of 100,000;

(4) Perform electrospinning on the outer surface of the Type II electrospun fiber membrane to form another layer of Type I electrospun fiber membrane with a thickness of 300 microns and an average pore size of 2.9 microns, thereby obtaining a surface-modified scaffold;

The process parameters of electrospinning are: the concentration of the spinning solution is 15wt%, the spinning voltage is 20kV, the spinning advancement speed is 1.5mL/h, the diameter of the cylinder receiving the substrate is 7mm, the receiving distance is 15cm, and the rotation speed is 200rpm;

The polymer in the spinning solution is polyurethane with a number average molecular weight of 200,000;

The prepared surface-modified stent is a tubular stent with a composite layer structure. The composite layer has a total of 3 layers. The inner and outer layers are both type I electrospun fiber membrane layers, and the middle layer is a type II electrospinning fiber membrane layer; The inner and outer surfaces of the inner layer are grafted with heparin/bFGF, while the inner and outer surfaces of the middle layer and outer layer are not grafted with heparin/bFGF.

The final surface-modified stent can be used as a large blood vessel stent. Both the inner and outer surfaces of the inner layer are grafted with heparin/bFGF. Heparin can play an anticoagulant effect, and the combined bFGF promotes the intima of the stent through slow release. Endothelialization, thereby building new vascular tissue faster. Since heparin/bFGF exists on both the inner and outer surfaces of the inner layer of the stent, and there is a fiber isolation layer with very small pore size II (i.e., type II electrospun fiber membrane layer), the bFGF stored on the outer surface of the inner layer is basically It is unidirectionally slowly released into the stent lumen through the pores, thus prolonging the action time of bFGF for 3 to 4 weeks.

Example 8

A method for preparing a surface-modified stent. The specific steps are as follows:

(1) Using a cylinder as the receiving base material, perform electrospinning on its peripheral surface to form a layer of Class I electrospun fiber membrane with a thickness of 300 microns and an average pore diameter of 3.2 microns;

The process parameters of electrospinning are: the concentration of the spinning solution is 15wt%, the spinning voltage is 20kV, the spinning advancement speed is 1mL/h, the diameter of the cylinder receiving the substrate is 25mm, the receiving distance is 15cm, and the rotation speed is 250rpm;

The polymer in the spinning solution is polycaprolactone with a number average molecular weight of 400,000;

(2) Aminolysis-grafting modification of type I electrospun fiber membrane;

The process of aminolysis-grafting modification is as follows: first, place the type I electrospun fiber membrane in a n-propanol solution of hexamethylenediamine with a mass-to-volume ratio of 6g/100mL, and then perform an aminolysis reaction at 50°C for 20 minutes. Finally, the product of the ammonolysis reaction, rebamipide and the aqueous solution of the cross-linking agent are mixed to perform a cross-linking reaction;

The mass ratio of rebamipide to the cross-linking agent is 10 ^-5 :1; the molar ratio of the active amino group on the product of the aminolysis reaction to the amino group on rebamipide is 1:1; the mass ratio of the cross-linking agent is 3:2 EDC and NHS, the concentration of the cross-linking agent aqueous solution is 5wt%; the cross-linking reaction temperature is 4°C and the time is 1 hour;

(3) Form a Type II electrospun fiber membrane with a thickness of 50 microns and an average pore size of 0.25 microns on the outer surface of the Type I electrospun fiber membrane through electrospinning;

The process parameters of electrospinning are: the concentration of spinning liquid is 8wt%, the spinning voltage is 8kV, the spinning advancement speed is 0.5mL/h, the diameter of the cylinder receiving the substrate is 25mm, the receiving distance is 8cm, and the rotation speed is 50rpm;

The polymer in the spinning solution is polyglycolic acid with a number average molecular weight of 50,000;

(4) Perform electrospinning on the outer surface of the Type II electrospun fiber membrane to form another layer of Type I electrospun fiber membrane with a thickness of 100 microns and an average pore size of 5.2 microns, to obtain a surface-modified scaffold;

The process parameters of electrospinning are: the concentration of the spinning solution is 15wt%, the spinning voltage is 20kV, the spinning advancement speed is 1mL/h, the diameter of the cylinder receiving the substrate is 25mm, the receiving distance is 15cm, and the rotation speed is 250rpm;

The polymer in the spinning solution is dioxanone with a number average molecular weight of 400,000;

The prepared surface-modified stent is a tubular stent with a composite layer structure. The composite layer has a total of 3 layers. The inner and outer layers are both type I electrospun fiber membrane layers, and the middle layer is a type II electrospinning fiber membrane layer; The inner and outer surfaces of the inner layer are grafted with rebamipide, while the inner and outer surfaces of the middle layer and the outer layer are not grafted with rebamipide.

The final surface-modified stent can be used as an esophageal stent, and rebamipide can repair the mucosa in the esophagus. The drug rebamipide is grafted on both the inner and outer surfaces of the stent, and the drug on the outer surface can continue to play a role later; the isolation layer in the middle layer (i.e., the type II electrospun fiber membrane layer) can also block fibroblasts. Role of invasion into the intima.

Example 9

A method for preparing a surface-modified stent is shown in Figure 5. The specific steps are as follows:

(1) Use a cylinder as the receiving base material and perform electrospinning on its peripheral surface to form a layer of Class I electrospinning fiber membrane with a thickness of 200 microns and an average pore diameter of 3.2 microns;

The process parameters of electrospinning are: the concentration of the spinning solution is 10wt%, the spinning voltage is 20kV, the spinning advancement speed is 1.2mL/h, the diameter of the cylinder receiving the substrate is 8mm, the receiving distance is 10cm, and the rotation speed is 100rpm;

The polymer in the spinning solution is polylactic acid with a number average molecular weight of 300,000;

(2) Aminolysis-grafting modification of type I electrospun fiber membrane;

The process of aminolysis-grafting modification is as follows: first, place the type I electrospun fiber membrane in a mixed solution of ethylenediamine, hexamethylenediamine in ethanol and n-propanol with a mass-to-volume ratio of 5g/5g/100mL/100mL. , then conduct an aminolysis reaction at 80°C for 1 minute, and finally mix the product of the aminolysis reaction, SNAP and the aqueous solution of the cross-linking agent to perform the cross-linking reaction;

The mass ratio of SNAP to cross-linking agent is 10 ^-2 :1; the molar ratio of the active amino group on the aminolysis reaction product to the carboxyl group on SNAP is 1:1; the cross-linking agent is EDC and EDC with a mass ratio of 3:2. NHS, the concentration of the cross-linking agent aqueous solution is 20wt%; the cross-linking reaction temperature is 4°C and the time is 0.6h;

(3) Form a non-porous casting layer with a thickness of 50 microns on the outer surface of the Class I electrospun fiber membrane through coating;

The material of the non-porous casting layer formed by the coating is hyaluronic acid gel. The specific preparation process is: disconnect the high-voltage power supply of the equipment used for electrospinning while keeping the receiving substrate continuing to rotate, and then add a concentration of 1wt% The hyaluronic acid aqueous solution is put into a syringe, extruded through a push pump, and deposited on the outer surface of the Class I electrospun fiber membrane; the number average molecular weight of hyaluronic acid is 1 million, and the extrusion speed is 3mL/h;

(4) Perform electrospinning on the outer surface of the non-porous casting layer to form another layer of Class I electrospun fiber membrane with a thickness of 240 microns and an average pore diameter of 3 microns, to obtain a surface-modified scaffold;

The process parameters of electrospinning are: the concentration of the spinning solution is 12wt%, the spinning voltage is 18kV, the spinning advancement speed is 1.4mL/h, the diameter of the cylinder receiving the substrate is 8mm, the receiving distance is 23cm, and the rotation speed is 180rpm;

The polymer in the spinning solution is polyurethane with a number average molecular weight of 200,000.

The prepared surface-modified stent is a tubular stent with a composite layer structure. The composite layer has a total of 3 layers. The inner and outer layers are both Class I electrospun fiber membrane layers, and the middle layer is a non-porous casting layer; the inner layer Both the inner and outer surfaces are grafted with SNAP, while the inner and outer surfaces of the middle layer and outer layer are not grafted with SNAP.

The final surface-modified stent can be used as a vascular stent. SNAP is grafted on the inner and outer surfaces of the inner layer. The SNAP on the outer surface is first stored without direct contact with blood, and then slowly releases NO and diffuses into the inner cavity through the pores. Prolong the action time; the middle casting layer strictly controls the direction of NO release from SNAP, so NO is released into the stent lumen in one direction, further improving the utilization efficiency of the drug at the target location.

Example 10

A method for preparing a surface-modified stent. The specific steps are as follows:

(1) Use a cylinder as the receiving base material and perform electrospinning on its peripheral surface to form a layer of Class I electrospinning fiber membrane with a thickness of 200 microns and an average pore diameter of 3.8 microns;

The process parameters of electrospinning are: the concentration of the spinning solution is 10wt%, the spinning voltage is 20kV, the spinning advancement speed is 1.8mL/h, the diameter of the cylinder receiving the substrate is 19mm, the receiving distance is 12cm, and the rotation speed is 150rpm;

The polymer in the spinning solution is polycaprolactone with a number average molecular weight of 400,000;

(2) Aminolysis-grafting modification of type I electrospun fiber membrane;

The process of aminolysis-grafting modification is: first, place the type I electrospun fiber membrane in a mixed solution of ethylenediamine, hexamethylenediamine, ethanol and isopropyl alcohol with a mass-volume ratio of 6g/6g/100mL/100mL. in, then perform an aminolysis reaction at 50°C for 20 minutes, and finally mix the product of the aminolysis reaction, the cephalosporin and the aqueous solution of the cross-linking agent to perform the cross-linking reaction;

The mass ratio of cephalosporin and cross-linking agent is 10 ^-5 :1; the molar ratio of the active amino group on the product of the aminolysis reaction and the carboxyl group on the cephalosporin is 1:1; the mass ratio of the cross-linking agent is 3: 2 EDC and NHS, the concentration of the cross-linking agent aqueous solution is 5wt%; the cross-linking reaction temperature is 4°C and the time is 0.7h;

(3) After completely wrapping the circumference of the cylinder with tin foil, put the Type I electrospun fiber membrane on the cylinder again and continue to coat the outer surface of the Type I electrospun fiber membrane to a thickness of 100 Micron non-porous casting layer;

The material of the non-porous casting layer formed by the coating is alginic acid gel. The specific preparation process is as follows: disconnect the high-voltage power supply of the equipment used for electrospinning while keeping the receiving substrate continuing to rotate. The alginic acid polysaccharide aqueous solution is put into a syringe, extruded through a push pump, and deposited on the outer surface of the Class I electrospinning fiber membrane; the number average molecular weight of the alginic acid polysaccharide is 200,000, and the extrusion speed is 5mL/h;

(4) Perform electrospinning on the outer surface of the non-porous casting layer to form another layer of Class I electrospun fiber membrane with a thickness of 240 microns and an average pore diameter of 3.6 microns, to obtain a stent intermediate product;

The process parameters of electrospinning are: the concentration of the spinning solution is 12wt%, the spinning voltage is 20kV, the spinning advancement speed is 1.5mL/h, the diameter of the cylinder receiving the substrate is 18.8mm, the receiving distance is 21cm, and the rotation speed is 170rpm;

The polymer in the spinning solution is dioxanone with a number average molecular weight of 400,000.

(5) Remove the product of step (4) containing tin foil from the cylinder, perform ammonolysis-grafting modification, and then remove the tin foil to obtain a surface-modified stent;

The process of aminolysis-graft modification of the product of step (4) containing tin foil paper is basically the same as the process of aminolysis-graft modification of the first layer of type I electrospun fiber membrane. The only difference is that Replace cephalosporins with salvianolic acid.

The prepared surface-modified stent is a tubular stent with a composite layer structure. The composite layer has a total of 3 layers. The inner and outer layers are both Class I electrospun fiber membrane layers, and the middle layer is a non-porous casting layer; the inner layer Both the inner and outer surfaces are grafted with cephalosporins, and only the outer surface of the outer layer is grafted with salvianolic acid.

The final surface-modified stent can be used as a tracheal stent. Cephalosporins have antibacterial and anti-inflammatory effects, and the introduction of salvianolic acid can prevent excessive fibrosis of the stent. Since both the inner and outer surfaces of the inner layer of the stent are grafted with cephalosporins, the drugs on the inner surface can take effect in the early stages of stent implantation, while the drugs on the outer surface will take effect in the middle and later stages to ensure the smoothness of the tissue repair process.

Examples 11-12

A method for preparing a surface-modified stent is basically the same as in Example 2, except that the functional substances in Examples 11 to 12 are not the SNAP of Example 2, but are indomethacin and naproxen respectively.

Examples 13 to 17

A method for preparing a surface-modified stent, which is basically the same as Example 4. The only difference is that the functional substances in Examples 13 to 17 are not the gentamicin of Example 4, but are amikacin and netilib respectively. star, minor nomicin, isopamicin and etimicin.

Example 18

A method for preparing a surface-modified stent. The specific steps are as follows:

(1) Using a cylinder as the receiving substrate, perform electrospinning on its peripheral surface to form a layer of Class I electrospun fiber membrane with a thickness of 100 microns and an average pore diameter of 5.4 microns;

The process parameters of electrospinning are: the concentration of spinning liquid is 8wt%, the spinning voltage is 10kV, the spinning advancement speed is 1mL/h, the diameter of the cylinder receiving the substrate is 10mm, the receiving distance is 8cm, and the rotation speed is 50rpm;

The polymer in the spinning solution is polylactic acid with a number average molecular weight of 500,000;

(2) Remove the Type I electrospun fiber membrane from the cylinder and perform ammonolysis-grafting modification of the Type I electrospun fiber membrane;

The process of aminolysis-graft modification is as follows: first, place the type I electrospinning fiber membrane in a n-propanol solution of hexamethylenediamine with a mass-to-volume ratio of 10g/100mL, and then perform an aminolysis reaction at 80°C for 1 minute. Finally, the product of the ammonolysis reaction, norfloxacin and the cross-linking agent aqueous solution are mixed and the cross-linking reaction is performed;

The mass ratio of norfloxacin and cross-linking agent is 10 ^-5 :1; the molar ratio of the active amino group on the product of the aminolysis reaction and the carboxyl group on norfloxacin is 1:1; the mass ratio of the cross-linking agent is 3:2 EDC and NHS, the concentration of the cross-linking agent aqueous solution is 5wt%; the cross-linking reaction temperature is 4°C and the time is 0.8h;

(3) After completely wrapping the circumference of the cylinder with tin foil, put the Type I electrospinning fiber membrane on the cylinder again and continue electrospinning on the outer surface of the Type I electrospinning fiber membrane to form another Type I electrospun fiber membrane with a layer thickness of 300 microns and an average pore size of 3.3 microns;

The process parameters of electrospinning are: the concentration of spinning liquid is 8wt%, the spinning voltage is 10kV, the spinning advancement speed is 1mL/h, the diameter of the cylinder receiving the substrate is 9.8mm, the receiving distance is 8cm, and the rotation speed is 50rpm;

The polymer in the spinning solution is polycaprolactone with a number average molecular weight of 500,000;

(4) Remove the tin foil paper from the cylinder, perform ammonolysis-graft modification on the product of step (3) containing the tin foil paper, and then remove the tin foil paper to obtain a surface-modified stent precursor;

The process of aminolysis-graft modification of the product of step (3) containing tin foil paper is basically the same as the process of aminolysis-graft modification of the first layer of type I electrospun fiber membrane. The only difference is that Use danshensu instead of norfloxacin;

(5) Cut and spread the stent precursor composed of two layers of Class I electrospun fiber membranes along the axial direction of the stent precursor to obtain a surface-modified stent.

The prepared surface-modified stent is a sheet-like stent with a composite layer structure. The composite layer has a total of 2 layers, both of which are Class I electrospun fiber membrane layers. Both surfaces of the first layer are grafted with norfloxacin. Star, only the outer surface of the second layer is grafted with salvianoside.

The final surface-modified stent can be used as a dressing. The inner and outer layers of the first layer are grafted with a drug, norfloxacin, to have a sustained anti-inflammatory effect, and the outer layer is grafted with a drug, Danshensu, to inhibit fibrosis. Effective, inhibit scarring. The drugs on both sides are different and have different effects according to the tissue repair process to accelerate tissue healing.

Example 19

A method for preparing a surface-modified stent. The specific steps are as follows:

(1) Using a cylinder as the receiving base material, perform electrospinning on its peripheral surface to form a layer of Class I electrospinning fiber membrane with a thickness of 400 microns and an average pore size of 2.8 microns;

The process parameters of electrospinning are: the concentration of the spinning solution is 10wt%, the spinning voltage is 20kV, the spinning advancement speed is 1.8mL/h, the diameter of the cylinder receiving the substrate is 20mm, the receiving distance is 12cm, and the rotation speed is 150rpm;

The polymer in the spinning solution is polycaprolactone with a number average molecular weight of 400,000;

(2) Aminolysis-grafting modification of type I electrospun fiber membrane;

The process of aminolysis-grafting modification is: first, place the type I electrospun fiber membrane in a mixed solution of ethylenediamine, hexamethylenediamine, ethanol and isopropyl alcohol with a mass-volume ratio of 6g/6g/100mL/100mL. in, and then perform an aminolysis reaction at 50°C for 20 minutes, then mix the product of the aminolysis reaction, heparin and the aqueous solution of the cross-linking agent to perform the cross-linking reaction, and finally use an aqueous solution of the growth factor VEGF with a concentration of 150ng/mL to infiltrate and cross-link On the surface of the reaction product for 30 minutes, heparin binds to VEGF growth factor (the product is recorded as heparin/VEGR);

Among them, the mass ratio of heparin to the cross-linking agent is 10 ^-5 :1; the molar ratio of the active amino group on the aminolysis reaction product to the carboxyl group on the heparin is 1:1; the cross-linking agent is a mass ratio of 3:2 For EDC and NHS, the concentration of the cross-linking agent aqueous solution is 5wt%; the cross-linking reaction temperature is 4°C and the time is 0.9h;

(3) After completely wrapping the circumference of the cylinder with tin foil, put the Type I electrospinning fiber membrane on the cylinder again and continue electrospinning on the outer surface of the Type I electrospinning to form another layer with a thickness of 60 micron type I electrospun fiber membrane with an average pore size of 6.3 micron;

The process parameters of electrospinning are: the concentration of the spinning solution is 12wt%, the spinning voltage is 20kV, the spinning advancement speed is 1.5mL/h, the diameter of the cylinder receiving the substrate is 19.8mm, the receiving distance is 21cm, and the rotation speed is 170rpm;

The polymer in the spinning solution is dioxanone with a number average molecular weight of 400,000;

(4) Remove the product of step (3) containing the tin foil paper from the cylinder, then perform ammonolysis-graft modification and then remove the tin foil paper to obtain a surface-modified stent precursor;

The process of aminolysis-graft modification of the product of step (3) containing tin foil paper is basically the same as the process of aminolysis-graft modification of the first layer of type I electrospun fiber membrane. The only difference is that Use ibuprofen instead of heparin, and omit the infiltration with an aqueous solution of the growth factor VEGF;

(5) Cut the stent precursor composed of two layers of Class I electrospun fiber membranes along the axial direction and spread it to obtain a surface-modified stent.

The prepared surface-modified stent is a sheet-like stent with a composite layer structure. The two composite layers are both type I electrospun fiber membrane layers; both surfaces of the first layer are grafted with heparin/VEGF, and the second surface is grafted with heparin/VEGF. Only the outer surface of the layer is grafted with ibuprofen.

The final surface-modified stent can be used as a heart or blood vessel patch, grafted with different drugs. Heparin/VEGF can prevent platelet adhesion and promote endothelialization, and ibuprofen can reduce inflammation and reduce immune rejection. Since both surfaces of the first layer of the stent are grafted with heparin/VEGF, the effect is similar to the previous case. It can extend the action time of VEGF for 3 to 4 weeks and better promote tissue repair.

Claims (4)

1. A surface-modified stent, characterized in that the surface-modified stent is a tubular stent with a total of 2 composite layers, both of which are Class I electrospun fiber membrane layers; both the inner and outer surfaces of the inner layer are grafted There are functional substances, the inner and outer surfaces of the outer layer are not grafted with functional substances, and the functional substances are SNAP; the thickness of the outer layer is 3 to 5 times that of the inner layer, and the thickness of the inner layer is 50 to 100 microns; I The average pore size of the electrospinning-like fiber membrane layer is greater than 0.5 microns, and the material of the type I electrospinning fiber membrane layer is synthetic high molecular polymer; The preparation method of the surface-modified stent is as follows: first, electrospinning is performed on the peripheral surface of a cylinder using a cylinder as a receiving substrate to form a layer of Class I electrospinning fiber membrane, and then the Class I electrospinning fiber membrane is subjected to ammonium decomposition and splicing. Branch modification, and finally continue electrospinning on the outer surface of the Type I electrospinning fiber membrane to form another layer of Type I electrospinning fiber membrane, thereby obtaining a surface modified scaffold; The process of aminolysis-graft modification is as follows: first, place the Type I electrospinning fiber membrane in a diamine/alcohol solution to perform an aminolysis reaction to generate active amino groups, and then use a cross-linking agent to connect the functional substances to the active amino groups . 2. A surface-modified stent, characterized in that the surface-modified stent is a tubular stent with a total of 2 composite layers, both of which are Class I electrospun fiber membrane layers; only the outer surface of the inner layer is functionally grafted Substance, the inner and outer surfaces of the outer layer are not grafted with functional substances. The functional substances are substances that inhibit the excessive growth of smooth muscle cells; the thickness of the outer layer is 0.8~1.5 times that of the inner layer, and the thickness of the inner layer is 200~300 Micron; the average pore diameter of the Type I electrospinning fiber membrane layer is greater than 0.5 micron, and the material of the Type I electrospinning fiber membrane layer is synthetic high molecular polymer; The preparation method of the surface-modified stent is as follows: first, a cylinder is used as the receiving base material and electrospinning is performed on its peripheral surface to form a layer of Class I electrospinning fiber membrane. The peripheral surface of the cylinder is completely wrapped with the water-proof conductive film, and then together with the After removing the type I electrospinning fiber membrane together with the water-proof conductive membrane, the type I electrospinning fiber membrane is subjected to ammonolysis-grafting modification, and finally electrospinning is continued on the outer surface of the type I electrospinning fiber membrane. Form another layer of Class I electrospinning fiber membrane to obtain a surface-modified scaffold; The process of aminolysis-graft modification is as follows: first, place the Type I electrospinning fiber membrane in a diamine/alcohol solution to perform an aminolysis reaction to generate active amino groups, and then use a cross-linking agent to connect the functional substances to the active amino groups . 3. A surface-modified stent, characterized in that the surface-modified stent is a tubular stent with a total of 2 composite layers, both of which are Class I electrospun fiber membrane layers; only the outer surface of the inner layer is functionally grafted Substance, only the outer surface of the outer layer is grafted with functional substances. Functional substances are substances that can function after the surface-modified scaffold contacts tissue fluid; the thickness of the outer layer is 20~60 microns, and the thickness of the inner layer is 300~500 Micron; the average pore diameter of the Type I electrospinning fiber membrane layer is greater than 0.5 micron, and the material of the Type I electrospinning fiber membrane layer is synthetic high molecular polymer; The preparation method of the surface-modified stent is as follows: first, electrospinning is performed on the peripheral surface of a cylinder using a cylinder as a receiving substrate to form the first layer of Class I electrospinning fiber membrane. The peripheral surface of the cylinder is completely wrapped with a water-proof conductive film, and then After removing the first layer of Type I electrospun fiber membrane together with the water-proof conductive film, the first layer of Type I electrospun fiber membrane is subjected to ammonolysis-grafting modification, and then without removing the water-proof conductive film Next, electrospinning is continued on the outer surface of the first layer of Class I electrospinning fiber membrane to form a second layer of Class I electrospinning fiber membrane to obtain an intermediate product containing a water-proof conductive film, and finally the intermediate product containing a water-proof conductive film is The product is subjected to ammonolysis-grafting modification and then the water-isolating conductive film is removed to obtain a surface-modified stent; The process of ammonolysis-graft modification is as follows: first, place the first layer of Class I electrospinning fiber membrane or the intermediate product containing a water-barrier conductive membrane in a diamine/alcohol solution to perform an ammonolysis reaction to generate active amino groups, and then Use cross-linking agents to connect functional substances with active amino groups. 4. A surface-modified stent, characterized in that the surface-modified stent is a tubular stent with a total of 3 composite layers. The inner and outer layers are both type I electrospinning fiber membrane layers, and the middle layer is type II electrospinning. Silk fiber membrane layer or non-porous casting layer; the inner and outer surfaces of the inner layer are grafted with functional substances, and the inner and outer surfaces of the outer layer are not grafted with functional substances. Class II electrospinning fiber membrane layer and The surface of the non-porous pouring layer is not grafted with functional substances, and the functional substance is SNAP; the thickness of the outer layer is 100~300 microns, the thickness of the middle layer is 50~120 microns, and the thickness of the inner layer is 100~300 microns. ;The average pore size of the Type I electrospinning fiber membrane layer is greater than 0.5 microns, and the average pore size of the Type II electrospinning fiber membrane layer is ≤0.5 microns; The material of the Type I electrospinning fiber membrane layer is synthetic high molecular polymer; The preparation method of the surface-modified stent is as follows: first, electrospinning is performed on the peripheral surface of a cylinder using a cylinder as a receiving substrate to form a layer of Class I electrospinning fiber membrane, and then the Class I electrospinning fiber membrane is subjected to ammonium decomposition and splicing. Branch modification, then electrospinning on the outer surface of the type I electrospinning fiber membrane to form a type II electrospinning fiber membrane, or forming a non-porous casting layer through coating, and finally forming a type II electrospinning fiber membrane or The outer surface of the non-porous casting layer is electrospun to form another layer of Class I electrospun fiber membrane, which is a surface-modified scaffold; The process of aminolysis-graft modification is as follows: first, place the Type I electrospinning fiber membrane in a diamine/alcohol solution to perform an aminolysis reaction to generate active amino groups, and then use a cross-linking agent to connect the functional substances to the active amino groups .